The 63rd-ranked Lepchenko never had made it beyond the second round at any Grand Slam tournament.
But she rallied to eliminate Schiavone, who was the runner-up at last year's French Open, in a match that lasted 3 hours, 2 minutes.
Lepchenko joins Sloane Stephens, who won Friday, to give the U.S. two unseeded women in the fourth round at a major tournament for the first time since Wimbledon in 2002.
She had 44 unforced errors against Schiavone, but still managed to advance.
"It's her court, you know," Lepchenko said. "I knew that she's not going to give it for free. I had to work really hard, and I did."
Lepchenko was born in Uzbekistan and now lives in Allentown, Pa. She became a U.S. citizen last year.
Sharapova moved into the round of 16 with a 6-2, 6-1 victory over Peng Shuai.
"In the next round, it starts from 0-0. Whoever you're playing, you have to go and try and do the same thing," Sharapova said. "There are a lot more rounds to go. It just gets tougher from this point."
Sharapova, who needs a championship at Roland Garros to complete the career Grand Slam, has lost only five games in three matches so far in Paris.
Li needed three sets to stop American Christina McHale.
The seventh-seeded Li, who last year became the first Chinese player to win a Grand Slam singles title, rallied to beat McHale 3-6, 6-2, 6-1.
Li committed 44 unforced errors in her match, 20 more than her unseeded opponent.
The last woman to successfully defend her title at Roland Garros was Justine Henin, who won three straight from 2005-07.
Meanwhile, Wozniacki lost to Kaia Kanepi of Estonia 6-1, 6-7 (3) 6-3, calling the officiating a "disgrace" after her third-round exit.
The Dane argued several line calls, including a ball that was judged to have hit the baseline early in the second set.
"It's a disgrace that mistakes like this are made," Wozniacki said. "It wasn't even like, 'Could have been in, could have been out.' It was clearly out."
The call came at 1-1 in the second set with Kanepi holding a break point. Wozniacki argued with chair umpire Poncho Ayala of Spain, who agreed with the original call that the ball hit the line.
"How can you sit there and be so arrogant?" Wozniacki said to Ayala. "Have you gone to school?"
After coming back to win the second set, Wozniacki again argued a line call in the third.
Kanepi, who finally won on her fifth match point despite being broken four times while serving for the match, said she wasn't affected by the uproar.
"Well, I think that those things happen in tennis matches, so it's OK if she wants to argue," Kanepi said. "I have to be ready for that and take it easy."
Wozniacki finished the last two years as the top-ranked player but has never won a Grand Slam title. Her best result at a major tournament was a runner-up finish at the 2009 U.S. Open.
Wozniacki has dropped to No. 9 in the rankings and has not won a title yet this year. She recently hired 2002 Australian Open champion Thomas Johansson as coach.
Kvitova is the only player ranked in the top 10 that has not yet reached a final this year. But she missed some tournaments with injury and illness.
"I had already a tough season. After Australia I was really injured and I couldn't play," said Kvitova, who won her first Grand Slam title at last year's Wimbledon. "So I'm happy that I can play right now and I can be healthy and play my tennis again."
Information from The Associated Press was used in this report.